Materials that gel in situ have recently gained attention as promising implantable drug delivery systems as well as injectable matrices for tissue engineering. There is an emerging need for materials that are biocompatible, promote cellular proliferation and biosynthesis, support physiological loads, and are easily manipulated and synthesized. Materials that gel in situ are promising as they are easily handled and permit cell seeding; they offer the ability to form any desired implant shape, and may be engineered to be biodegradable and biocompatible.
In situ gelation is the bases of injectable systems that eliminate the need for surgical procedures and offers the advantage of the ability to form any desired implant shape. The change in molecular association can be driven by changes in temperature, pH, or solvent composition. Among the candidates of stimuli sensitive systems, organic solvent-free injectable systems are designed by using the thermosensitive sol-to-gel transition of aqueous solution. Such a system enables bioactive agents to be easily entrapped.
To perform as an ideal injectable system, the aqueous solution of a polymer should exhibit low viscosity at formulation conditions and gel quickly at physiological conditions. Considering the biomedical applications, the biocompatibility of the polymers is also an important issue. Therefore, the material should be biodegradable, and by keeping water-rich hydrogel properties it should not induce tissue irritation during the degradation.
In situ gelling of aqueous Poloxamer 407 and N-isopropylacrylamide copolymers have been studied as candidate materials for injectable drug delivery systems and also tissue engineering applications. These materials are, however, non-biodegradable and animal studies demonstrated an increase in triglyceride and cholesterol after intraperitoneal injection of the aqueous Poloxamer 407 solution.9 
Other reported thermogelling drug delivery materials include N-isopropylacryl amide copolymers, poly(acrylic acid)-g-POLOXAMER (SMART GEL), chitosan/glycerol phosphate, and poly(ethylene glycol)/poly(lactic acid-co-glycolic acid). Aqueous solutions of such materials undergo sol-to-gel transitions with increasing temperatures. A formulation having a sol-phase at a relatively low temperature and a gel-phase at body temperature is preferable for an injectable, in-situ gel-forming depot for drug delivery and tissue engineering applications.
Recently, Jeong et al. reported biodegradable, in situ gelling poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol), (PEG-PLGA-PEG), triblock copolymers. (See U.S. Pat. No. 6,117,949) They exhibited promising properties as an injectable drug delivery system. In vivo studies in rats demonstrated that the copolymer gels were still present after one month. During the degradation, the initially transparent gel became opaque due to preferential mass-loss of hydrophilic PEG rich segments. This change in morphology and the generation of an interface or phase might denature the protein drugs or cause cell deterioration in tissue engineering. In vitro release of porcine growth hormone (PGH) and insulin from the in-situ formed gel stopped after releasing 40–50% of loaded proteins.
Recently, several protein/peptide drugs demonstrated excellent efficacy in clinical trials and have been introduced to the market. With the advent of genetic engineering, proteins/peptides will soon become much more common drugs. However, due to the short plasma half-life and instability of proteins, there are urgent needs for suitable delivery vehicles. Certain drug formulations need a one to two-week delivery system. Moreover, a one to two-day delivery system may be required. For example, ifosfamide, a drug used for germ cell testicular cancer, is administered intravenously for 5 consecutive days. This treatment is repeated every three weeks or after recovery from hematological toxicity. In order to prepare such a short-term delivery system, poly(ethylene glycol) grafted with poly(lactic acid-co-glycolic acid) (PEG-g-PLGA), where hydrophilic PEG is a backbone, is designed. This material is expected to show a different gelation and degradation behavior, and consequently, a different drug release profile as compared to PEG-PLGA-PEG.
The following references disclose processes or compounds useful in this art:    U.S. Pat. No. 5,702,717    U.S. Pat. No. 5,117,949    Hill-West, J. L.; Chowdhury, S. M.; Slepian, M. J.; Hubbell, J. A. Proc. Natl. Acad. Sci. USA, 1994, 91, 5967–5971.    Stile, R. A.; Burghardt, W. R.; Healy, K. E. Macromolecules, 1999, 32, 7370–7379.    Chen, G. H.; Hoffman, A. S.; Nature, 1995, 373, 49–52.    Thomas, J. L.; You, H.; Tirrell, D. J. Am. Chem. Soc., 1995, 117, 2949–2950.    Malstom, M.; Lindman, B. Macromolecules, 1992, 25, 5446–5450.    Yang, J.; Pickard, S.; Deng, N. J.; Barlow, R. J.; Attwood, D.; Booth, C. Macromolecules, 1994, 27, 670–680.    Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Nature, 1997, 388, 860–862.    Johnston, T. P.; Punjabi, M. A.; Froelich, C. J. Pharm. Res., 1992, 9(3), 425–434.    Wout, Z. G. M.; Pec, E. A.; Maggiore, J. A.; Williams, R. H.; Palicharla, P.; Johnston, T. P. J. Parenteral Sci. & Tech., 1992, 46(6), 192–200.    Jeong, B.; Bae, Y. H.; Kim, S. W. J. Controlled Releases, 2000, 63, 155–163.    Jeong, B.; Bae, Y. H.; Kim, S. W. J. Biomed. Mater. Res, 2000, 50 (2), 171–177.    Jeong, B.; Gutowska, A. J. Am. Chem. Soc., 2000, Submitted.    Jeong, B. Unpublished Data. 2000.    IFEX Prescription, http://www.ifex.com/ifpre.html, A Bristol-Meyers Squibb Co., Princeton, N.J. 08543    Bellare, J. R.; Davis, H. T.; Scriven, L. E.; Talmon, Y. J. Electron Microsc. Tech. 1988, 10, 87–111.    Wanka, G.; Hoffmann, H.; Ulbricht, W. Colloid Polym. Sci., 1990, 268, 101–117.    Tanodekaew, S.; Godward, J.; Heatley, F.; Booth, C. Macromol. Chem. Phys., 1997, 198, 3385–3395.    Odian, G. In Principles of Polymerization, 2nd ed.; John Wiley & Sons, Inc. Korean Student Ed.: Korea, 1981; p 513.    Alexandrisdis, P.; Holzwarth, J. F.; Hatton, T. A. Macromolecules, 1994, 27, 2414–2425.    Discher, B. M.; Won, Y.-Y.; Ege, D. S.; Lee, J. C. M.; Bates, F. S.; Discher, D. E.; Hammer, D. A. Science, 1999, 284, 1143–1146.    Won, Y.-Y.; Davis, H. T.; Bates, F. S. Science, 1999, 283, 960–963.    Brown, W.; Schillen, K.; Almgren, M.; Hvidt, S.; Bahadur, P. J. Phys. Chem., 1991, 95, 1850–1858.    Cau F.; Lacelle, S. Macromolecules, 1996, 29, 170–178.    Jeong, B.; Bae, Y. H.; Kim, S. W. Colloids and Surfaces B: Biointerfaces, 1999, 16: 185–193.    Zhou, Z.; Chu, B. J. colloid and Interface Science, 1988, 126(1): 171–180.    Deng, Y.; Yu, G. E.; Price, C.; Booth, C. J. Chem. Soc. Faraday Trans. 1992, 88(10), 1441–1446.    Yu, G. E.; Deng, Y.; Dalton, S.; Wang, Q. G.; Attwood, D.; Price, C.; Booth, C. J. Chem. Soc., Faraday Trans. 1992, 88 (17), 2537–2544.    Jeong, B.; Bae, Y. H.; Kim, S. W. Macromolecules 1999, 32, 7064–7069.    Israelachivili, J. N. Intermolecular and Surface Forces, Academic Press, New York, 1985.    Feil, H.; Bae, Y. H.; Feijen, J.; Kim, S. W. Macromolecules, 1993, 26, 2496–2500.    Jeong, B.; Lee, D. S.; Shon, J. I.; Bae, Y. H.; Kim, S. W. J. Polym. Sci. Polym. Chem. 1999, 37, 751–760.